tbuckley/cabot-search huggingface dataset:
First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817
Authors: Neal E Ready, Clarisse Audigier-Valette, Jonathan W Goldman, Enriqueta Felip, Tudor-Eliade Ciuleanu, María Rosario García Campelo, Kevin Jao, Fabrice Barlesi, Stéphanie Bordenave, Erika Rijavec, Laszlo Urban, Jean-Sébastien Aucoin, Cristina Zannori, Karim Vermaelen, Osvaldo Arén Frontera, Alessandra Curioni Fontecedro, Amparo Sánchez-Gastaldo, Oscar Juan-Vidal, Helena Linardou, Elena Poddubskaya, David R Spigel, Samreen Ahmed, Michele Maio, Sunney Li, Han Chang, Joseph Fiore, Angelic Acevedo, Luis Paz-Ares
Journal: Journal for ImmunoTherapy of Cancer (2023)

CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0-1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3-4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.The most common grade 3-4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3-4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0-1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.NCT02869789.
A cellular taxonomy of the adult human spinal cord
Authors: Archana Yadav, Kaya J.E. Matson, Li Li, Isabelle Hua, Joana Petrescu, Kristy Kang, Mor R. Alkaslasi, Dylan I. Lee, Saadia Hasan, Ahmad Galuta, Annemarie Dedek, Sara Ameri, Jessica Parnell, Mohammad M. Alshardan, Feras Abbas Qumqumji, Saud M. Alhamad, Alick Pingbei Wang, Gaetan Poulen, Nicolas Lonjon, Florence Vachiery-Lahaye, Pallavi Gaur, Mike A. Nalls, Yue A. Qi, Dragan Maric, Michael E. Ward, Michael E. Hildebrand, Pierre-Francois Mery, Emmanuel Bourinet, Luc Bauchet, Eve C. Tsai, Hemali Phatnani, Claire E. Le Pichon, Vilas Menon, Ariel J. Levine
Journal: Neuron (2023)

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding of spinal cellular diversity, characterizing human biology directly is important to uncover specialized features of basic function and human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single-nucleus RNA sequencing with spatial transcriptomics and antibody validation. We identified 29 glial clusters and 35 neuronal clusters, organized principally by anatomical location. To demonstrate the relevance of this resource to human disease, we analyzed spinal motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) and other diseases. We found that compared with other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, suggesting a specialized molecular repertoire underlying their selective vulnerability. We include a web resource to facilitate further investigations into human spinal cord biology.
Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells
Authors: Feng Tian, Yuyan Cheng, Songlin Zhou, Qianbin Wang, Aboozar Monavarfeshani, Kun Gao, Weiqian Jiang, Riki Kawaguchi, Qing Wang, Mingjun Tang, Ryan Donahue, Huyan Meng, Yu Zhang, Anne Jacobi, Wenjun Yan, Jiani Yin, Xinyi Cai, Zhiyun Yang, Shane Hegarty, Joanna Stanicka, Phillip Dmitriev, Daniel Taub, Junjie Zhu, Clifford J. Woolf, Joshua R. Sanes, Daniel H. Geschwind, Zhigang He
Journal: Neuron (2023)
Insulin Deficiency From Insulin Gene Mutation Leads to Smaller Pancreas
Authors: Jordan J. Wright, Jonathan M. Williams, Lisa R. Letourneau-Freiberg, Balamurugan Kandasamy, Demetra Reyes, Anastasia Gant Kanegusuku, Louis Philipson, Siri Atma W. Greeley, Melissa A. Hilmes, Alvin C. Powers, John Virostko, Daniel J. Moore
Journal: Diabetes Care (2023)

OBJECTIVE To determine the mechanism of reduced pancreas size in type 1 diabetes and the significance of islet-derived insulin in pancreatic growth. RESEARCH DESIGN AND METHODS Using a validated and standardized MRI protocol, we measured pancreas volume and shape in a family with an autosomal-dominant insulin gene mutation that results in insulin deficiency similar in severity to that of type 1 diabetes but without autoimmunity. DNA sequencing confirmed the mutation in all four affected individuals and none of the four control family members. Insulin secretory capacity was determined by measuring postprandial urinary C-peptide. RESULTS Family members with this form of monogenic diabetes had a markedly smaller pancreas and a severely impaired postprandial C-peptide level than family members without diabetes. CONCLUSIONS These results suggest that severe insulin deficiency, rather than islet-directed autoimmunity, leads to reduced pancreas size in type 1 diabetes and that insulin is a major trophic factor for the exocrine pancreas.
The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention
Authors: Seppe Cambier, Mieke Gouwy, Paul Proost
Journal: Cellular and Molecular Immunology (2023)

Abstract Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes. CXCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury. CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2, the atypical chemokine receptor ACKR1, and glycosaminoglycans. Furthermore, (hetero)dimerization and tight regulation of transcription and translation, as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer. The CXCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy, as illustrated by multiple ongoing clinical trials. CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12, which retains leukocytes in bone marrow. CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells, endothelial cells, and several leukocytes through interaction with CXCR4, ACKR1, and ACKR3. Thereby, it is an essential player in the regulation of embryogenesis, hematopoiesis, and angiogenesis. However, CXCL12 can also exert inflammatory functions, as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis. Here, we review the plethora of information on the CXCL8 structure, interaction with receptors and glycosaminoglycans, different levels of activity regulation, role in homeostasis and disease, and therapeutic prospects. Finally, we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.
Immunotherapies in rare cancers
Authors: Sneha Vivekanandhan, Deborah Bahr, Ashish Kothari, Mohammed Ali Ashary, Mizba Baksh, Emmanuel Gabriel
Journal: Molecular Cancer (2023)

Abstract Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers.
Digital health interventions for non-communicable disease management in primary health care in low-and middle-income countries
Authors: Shangzhi Xiong, Hongsheng Lu, Nicholas Peoples, Ege K. Duman, Alberto Najarro, Zhao Ni, Enying Gong, Ruoyu Yin, Truls Ostbye, Lia M. Palileo-Villanueva, Rinchen Doma, Sweta Kafle, Maoyi Tian, Lijing L. Yan
Journal: npj Digital Medicine (2023)

Current evidence on digital health interventions is disproportionately concerned with high-income countries and hospital settings. This scoping review evaluates the extent of use and effectiveness of digital health interventions for non-communicable disease (NCD) management in primary healthcare settings of low- and middle-income countries (LMICs) and identifies factors influencing digital health interventions' uptake. We use PubMed, Embase, and Web of Science search results from January 2010 to 2021. Of 8866 results, 52 met eligibility criteria (31 reviews, 21 trials). Benchmarked against World Health Organization's digital health classifications, only 14 out of 28 digital health intervention categories are found, suggesting critical under-use and lagging innovation. Digital health interventions' effectiveness vary across outcomes: clinical (mixed), behavioral (positively inclined), and service implementation outcomes (clear effectiveness). We further identify multiple factors influencing digital health intervention uptake, including political commitment, interactivity, user-centered design, and integration with existing systems, which points to future research and practices to invigorate digital health interventions for NCD management in primary health care of LMICs.
The collateral activity of RfxCas13d can induce lethality in a RfxCas13d knock-in mouse model
Authors: Yunfei Li, Junjie Xu, Xuefei Guo, Zhiwei Li, Lili Cao, Shengde Liu, Ying Guo, Guodong Wang, Yujie Luo, Zeming Zhang, Xuemei Wei, Yingchi Zhao, Tongtong Liu, Xiao Wang, Huawei Xia, Ming Kuang, Qirui Guo, Junhong Li, Luoying Chen, Yibing Wang, Qi Li, Fengchao Wang, Qinghua Liu, Fuping You
Journal: Genome biology (2023)

The CRISPR-Cas13 system is an RNA-guided RNA-targeting system and has been widely used in transcriptome engineering with potentially important clinical applications. However, it is still controversial whether Cas13 exhibits collateral activity in mammalian cells.
Cerebral Cystic Echinococcosis
Authors: Sumit Thakar, Akhil Sunil
Journal: New England Journal of Medicine (2023)

A 14-year-old boy who lived on a farm presented with episodic headaches associated with vomiting. MRI showed a large, multiloculated cyst in the brain, and a craniotomy (shown in a video) was performed to excise it.
Hypothermia or Machine Perfusion in Kidney Donors
Authors: Darren Malinoski, Christina Saunders, Sharon Swain, Tahnee Groat, Patrick R. Wood, Jeffrey Reese, Rachel Nelson, Jennifer Prinz, Kate Kishish, Craig Van De Walker, P.J. Geraghty, Kristine Broglio, Claus U. Niemann
Journal: New England Journal of Medicine (2023)

Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation.At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group). The primary outcome was delayed graft function in the kidney transplant recipients (defined as the initiation of dialysis during the first 7 days after transplantation). We also evaluated whether hypothermia alone was noninferior to machine perfusion alone and whether the combination of both methods was superior to each of the individual therapies. Secondary outcomes included graft survival at 1 year after transplantation.From 725 enrolled donors, 1349 kidneys were transplanted: 359 kidneys in the hypothermia group, 511 in the machine-perfusion group, and 479 in the combined-therapy group. Delayed graft function occurred in 109 patients (30%) in the hypothermia group, in 99 patients (19%) in the machine-perfusion group, and in 103 patients (22%) in the combination-therapy group. Adjusted risk ratios for delayed graft function were 1.72 (95% confidence interval [CI], 1.35 to 2.17) for hypothermia as compared with machine perfusion, 1.57 (95% CI, 1.26 to 1.96) for hypothermia as compared with combination therapy, and 1.09 (95% CI, 0.85 to 1.40) for combination therapy as compared with machine perfusion. At 1 year, the frequency of graft survival was similar in the three groups. A total of 10 adverse events were reported, including cardiovascular instability in 9 donors and organ loss in 1 donor owing to perfusion malfunction.Among brain-dead organ donors, therapeutic hypothermia was inferior to machine perfusion of the kidney in reducing delayed graft function after transplantation. The combination of hypothermia and machine perfusion did not provide additional protection. (Funded by Arnold Ventures; ClinicalTrials.gov number, NCT02525510.).
Risk prediction in MDS: independent validation of the IPSS-M—ready for routine?
Authors: Constance Baer, Sandra Huber, Stephan Hutter, Manja Meggendorfer, Niroshan Nadarajah, Wencke Walter, Uwe Platzbecker, Katharina S. Götze, Wolfgang Kern, Torsten Haferlach, Gregor Hoermann, Claudia Haferlach
Journal: Leukemia (2023)
Reply: Targeted decrease of portal hepatic pressure gradient immediately after TIPS improves ascites control and prognosis
Authors: Wenyi Gu, Alexander Queck, Jonel Trebicka, Michael Praktiknjo
Journal: Hepatology (2023)

We appreciate the interest of Tantai and colleagues in our work and share their aim to highlight the lack of guidance for targeted PPG for refractory ascites, which we addressed in our recent study published in Hepatology.1 We fully agree that studies are warranted to validate different etiologies of liver cirrhosis. However, in Germany and most western countries, alcohol-associated liver disease is still the leading cause of liver cirrhosis.2,3 The colleagues raised concerns about censored patients within a 6-week follow-up and suggested stratification of patients by PPG with survival as a direct endpoint. Since our study had ascites response as the primary outcome, all patients without information on paracentesis (n=19) had to be censored and we performed landmark analyses, which revealed targeted PPG reduction as a predictor for the outcome. Indeed, the survival analyses in our cohort suggests a significant association of ascites response with survival showing the lowest survival in patients with a continued need for paracentesis after TIPS. The best survival was observed in patients with ascites resolution after TIPS. Therefore, our study has a completely different and clinically more relevant focus in providing practical guidance for post-TIPS PPG in daily practice. However, despite the different focus, our data strongly suggests a significant association between PPG reduction, ascites response and survival in patients with recurrent and refractory ascites. Nevertheless, this discussion stimulated us to perform competing risk analysis for ascites response with death and liver transplantation as competing events, since 35 and 4 patients were censored for death and liver transplantation, respectively even before the 6 weeks. Indeed, our competing risk analysis adjusted for white blood cell count, Child-Pugh score and serum sodium confirmed our previous results of targeted PPG reduction as independent predictor of post-TIPS ascites response (HR=0.782, p=0.0151). Therefore, we are confident that the targeted pressure reduction provides robust clinical guidance for sufficient post-TIPS ascites response.
Ultrasmall PtAu<sub>2</sub> nanoclusters activate endogenous anti-inflammatory and anti-oxidative systems to prevent inflammatory osteolysis
Authors: Xuzhuo Chen, Xiankun Cao, Dasheng Zheng, Chang Li, Yan Chen, Keyu Kong, Weifeng Xu, Bin Shi, Xinwei Chen, Fengrong Dai, Shanyong Zhang
Journal: Theranostics (2023)

Rationale: Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation.Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases.Methods: In this study, heterometallic PtAu2 nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis.Results: PtAu2 clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent antiinflammatory and anti-OC activities in vitro.In addition, PtAu2 clusters alleviated lipopolysaccharide-induced calvarial osteolysis in vivo and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products.Conclusion: Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.
Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma: Erratum
Authors: Zhikui Liu, Yufeng Wang, Changwei Dou, Meng Xu, Liankang Sun, Liang Wang, Bowen Yao, Qing Li, Wei Yang, Kangsheng Tu, Qingguang Liu
Journal: Theranostics (2023)

[This corrects the article DOI: 10.7150/thno.26789.].
Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer
Authors: Fang-Lin Zhang, Shao-Ying Yang, Li Liao, Tai-Mei Zhang, Yin-Ling Zhang, Shu-Yuan Hu, Ling Deng, Min-Ying Huang, Lisa Andriani, Xiao-Yan Ma, Zhi-Min Shao, Da-Qiang Li
Journal: Theranostics (2023)

Rationale: SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents.Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy.MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic.Methods: In vivo and in vitro SUMOylation assays were used to determine the SUMOylation levels of MORC2.Overexpression and knockdown of SUMO-associated enzymes were used to detect their effects on MORC2 SUMOylation.The effect of dynamic MORC2 SUMOylation on the sensitivity of breast cancer cells to chemotherapeutic drugs was examined through in vitro and in vivo functional assays.Immunoprecipitation, GST pull-down, MNase, and chromatin segregation assays were used to explore the underlying mechanisms.Results: Here, we report that MORC2 is modified by small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 at lysine 767 (K767) in a SUMO-interacting motif dependent manner.MORC2 SUMOylation is induced by SUMO E3 ligase tripartite motif containing 28 (TRIM28) and reversed by deSUMOylase sentrin-specific protease 1 (SENP1).Intriguingly, SUMOylation of MORC2 is decreased at the early stage of DNA damage induced by chemotherapeutic drugs that attenuate the interaction of MORC2 with TRIM28.MORC2 deSUMOylation induces transient chromatin relaxation to enable efficient DNA repair.At the relatively late stage of DNA damage, MORC2 SUMOylation is restored, and SUMOylated MORC2 interacts with protein kinase CSK21 (casein kinase II subunit alpha), which in turn phosphorylates DNA-PKcs (DNA-dependent protein kinase catalytic subunit), thus promoting DNA repair.Notably, expression of a SUMOylation-deficient mutant MORC2 or administration of SUMO inhibitor enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs.Conclusions: Collectively, these findings uncover a novel regulatory mechanism of MORC2 by SUMOylation and reveal the intricate dynamics of MORC2 SUMOylation important for proper DDR.We also propose a promising strategy to sensitize MORC2-driven breast tumors to chemotherapeutic drugs by inhibition of the SUMO pathway.